1. Field of the Invention
Cancer is a disease of humans and animals which is for the most part fatal and which is caused by the uncontrolled growth of endogenous cells. Cancer is the term for the formation of malignant tumors (malignomas) and of neoplasms (tumors or carcinomas) or for the malignant degeneration and disturbed maturation of white blood cells (leukemia, blood cancer). Cancer cells or tumor cells arise as the result of the transformation of endogenous cells. The malignancy of the cancer cell is expressed in the autonomy of its growth, that is in the ability of the cell to grow in an uninhibited manner and without being fitted into the structure of the organs and also to grow in an infiltrating manner, thereby destroying tissue. The formation of disseminations (metastases) at a distance from the tumor, after tumor cells have been spread by way of the blood or the lymph, is a sure sign of malignancy. Cancer is one of the most frequent causes of death in humans and there is therefore a great need for methods and means for curing or treating malignant degenerations.
Aside from the, if possible radical, surgical removal of the tumor, the possibilities for treating malignant tumors include radiological therapy using X-rays, α-rays, β-rays and γ-rays, immunotherapy and chemotherapy. At present, immunotherapy can only be used to a limited extent. The chemotherapy of tumors is understood as meaning the administration of cell poisons (cytostatic agents) for treating tumors and tumor cells which remain, usually following local surgical treatment or irradiation. These substances interfere specifically in certain processes in cell division, which means that tissues containing a high proportion of dividing cells, such as rapidly growing tumor tissues, react more sensitively. The cytostatic agents which are used are alkylating compounds, such as cyclophosphamide, antimetabolites, such as methotrexate, alkaloids, such as vincristine, and antibiotics, such as daunomycin or adriamycin. However, due to massive side-effects, all these agents suffer from severe disadvantages, such that the death of the affected patient is only delayed and not averted. Furthermore, the degenerate (cancer) cells develop resistances to the agents which are used; while the medicaments which are being used at the time then no longer have any cytostatic effect, they are still toxic as a consequence of the side-effects. In addition, it has been found that the efficacy achieved by using cytostatic agents in combination or in sequence exceeds that achieved by using a single cytostatic agent (monotherapy) and, as a result, it is possible that the substantial side-effects are not additive in connection with polychemotherapy. For all these reasons, novel chemotherapeutic agents are urgently required and are therefore being sought world-wide.
2. Description of the Art
The first examples of bengamides were bengamides A and B, which are dodecanoyl-substituted on the caprolactam ring and which were isolated from the sea sponge Jaspis cf. Coriacea (family Coppatiidae, order Choristida B Astrophorida)(Adamczewski et al., J. Org. Chem. 1986, 51, 4497-4498) and reported to be biotoxic to eukaryotic cells, nematodes and bacteria.
Bengamide E
and its N-methylated derivative bengamide F are examples of bengamide derivatives which have been demonstrated to possess antitumor activity. Bengamide E inhibits cell proliferation by stopping cell division at the G1/S restriction point and in the G2/M phase of the cell cycle. Bengamide B derivatives inhibit the proliferation of MDA-MB-435 breast cancer cells (Kinder et al., J. Med. Chem. 2001, 44, 3692-3699).
A feature shared in common by the known bengamide derivatives is that they have been isolated from sea sponges of the genus Jaspis sp. or Pachastrissa sp. (Thale et al., J. Org. Chem. 2001, 66, 1733-1741).